Project Summary: Douglas W. White, MD, PhD did his graduate work in immunology and fellowship training in rheumatology. He is currently an Instructor at Washington University where works in the lab of Herbert Virgin and as an attending physician in the Division of Rheumatology. His immediate career goal is to establish an independent research enterprise at a major U.S. medical school studying the molecular mechanisms of herpesvirus latency and reactivation. His long-term career goals are to further our understanding of host-pathogen interactions, and continue his work as a medical educator and physician. The research community and resources at Washington University are fertile ground for young investigators. Dr. White's main mentors, Dr. Virgin and Dr. Wayne Yokoyama, are accomplished physician-scientists with outstanding track records for training post-doctoral fellows. This application outlines research in a novel system, in which Dr. White has unique expertise, to launch an independent career. The experiments are designed to improve our understanding of the mechanisms by which gammaherpesvirus maintain latency and reactivate to cause disease. The importance of this work is emphasized by the recent finding that herpesvirus latency, previously thought to be purely detrimental, confers a surprising benefit on the host. This finding suggests that efforts to limit the morbidity associated with herpesviruses cannot depend on eradication but will require a sophisticated understanding of the interactions between herpesviruses and their hosts. Previous studies in Dr. Virgin's laboratory identified a viral gene, known as M11, in murine gammaherpesvirus-68 (gHV68) that is necessary for efficient viral reactivation in vivo. Dr. White has extended this finding and developed a novel system in vitro to study the role of M11 during gHV68 infection of macrophages. His results to date establish gHV68 infection of macrophages in vitro as a model for latency and show that M11 enhances reactivation. The experiments in this application address the mechanism by which M11 exerts its effects. Aim 1 tests the hypothesis that M11 blocks apoptosis in infected cells while aims 2 &3 address a second, completely novel, hypothesis, that M11 exerts its effects by binding a cellular protein called Wapl. Many of the methods proposed are new for Dr. White and will thus enhance his experimental expertise. Relevance: "Herpes" refers to a family of viruses, including the one that causes cold sores, that infect all humans and cause diseases ranging from chicken pox to cancer. Just like herpes simplex virus, other herpesviruses cause the most harm not when they first infect their host, but when they reactivate after a period of relative dormancy (called "latency"). This research aims to understand, at a molecular level, how herpesviruses maintain latency and reactivate to cause disease.